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Publication numberUS2610185 A
Publication typeGrant
Publication dateSep 9, 1952
Filing dateNov 7, 1950
Publication numberUS 2610185 A, US 2610185A, US-A-2610185, US2610185 A, US2610185A
InventorsWilham Qroshnlk
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Oroshnik
US 2610185 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

Sept. 9, 1952 w, QRQSHNIK 2,610,185

Z-AMINO-4-DIALKYLAMINOPROPOXYPYRIMIDiNES Filed NOV. 7, 1950 I 2 SHEETS SHEET l v [Ni/ENTOR c i new 4 ATTOR EY S p 9, 1952 V w. OROSHNIK 2,610,135

2-AMINO4-DIALKYLAMINOPROPOXYPYRIMIDINES Filed Nov. 7, 1950 2 SHEETS-SHEET 2 a b ATTORNE V Patented Sept. 9, 1952 -smmowmstxrmnmomoroxra Pmmflmmus" William,:(lroshnih-Bl i fl N: J'-, ammon a: Qrtho, Ilxannaccutical;,Ccrporation;,.aacornorarionctblewlevscy ApplieationNoveinber 7, 1950,, Serial ism-194,500

This; invention: relates: to certain therapew' tically' effective organiccompounds which are derivatives of" isocytosine; 2ie-axnino t li'ydroiky-- pyrimidine;- and: to their use as therapeutic agents: having the: ability 1 to '5 stimulate contractions of the uterus: Morespecifically this invention' relates: to; z'eamino adialkylaminopror 2 bino rat-r uterine tissue: suspended: therein; "A continuous kymographicw record" was: madeof contractions of'the-uterine strip-before-andfafter poxypyrimidinesfin which: each alkyl group 'hasat leastt-hreafl and notrmoreth'an five,acarbon atoms; The said isocytosine derivitivesehaving thezabih ity to stimulate contractionsnctkthe uterus may be represented w by the following; tormula:

rivatiyes with organic or inorganic acids andsince the said derivatives are basic in character, theymay be readily converted into salts having substantially more solubility in water than the free bases. Salts such as the succinate, maleate, tartrate, lactate, fumarate and the like are preferred, but salts of simple low-molecular weight aliphatic organic acids as well as salts of the free bases with inorganic acids, may be readily prepared from the free bases and are highly effective therapeutically.

The new and novel derivatives of isocytosine to which the present invention is directed have considerable value which renders their use as pharmaceutical products highly advantageous either alone or with known pharmacological products. The ability of these novel substances to stimulate contractions of the uterus has been shown by a number of experiments in which a salt of isocytosine derivative was added to a bath of nutrient solution having a strip of a1- additiomto the bath of Pa salt of Fanuisoeytosine derivatives Additional? derivatives, of iSQOYbOssine-whichare-homologues of62 aminoi diallc'yls aminopropoxypyrimidines specifically mentioned before as havingtherapeutic value were P also testedgrinthe same wayitodetermine their effect on'contracti'onsof'theuterus; Water-soluble hydrochloridc saltsor the sesquisuccinate saltsi-:of the: followingojcompounds were n'tested i for their pharmacological" property or: stiniula'ting i contractionsnotithe uterusi eqmpoundgla zf; amino...+ 34 --di1 11- prowl: aminonropoxynyrimidme CompoundJIs-Z: amine-Andi. n=- amylaminopropoxypyrimidine V mp III.='-2... amino ,1 4- di..- .nbutylr aminopropoxypyrimidine qompoundlv z, amino 3. dimethylaminoethoxynyrimidine I (lomnound vwz amina 4 1. diethylaminoe ethoxynrr midine y a a Comppund,;VI-- 2. amino x. 4 diethylaminoe ethoxy 6 methylpyrimidine l The following procedure was employed in testingthe. eifect- 'of compounds-Pin on a rat uterus: A- female albino rat-weighing-from 150--30tl"mi1ligrams was=killed byablow-on-the head and the uterus=was-removedz A- strip of the-auterine tissue was suspended in a ccibathofana'erated Ringer-Locke solution-51' Gne end ofthemterine strip was-maintained in; astationary}- position amt-the otherend was: attached-tea levenwhich made contact with akymograph and continuously recorded contractions. After a short period of immersion in the bath, the strip of uterine tissue was contracting {rhythmically and normally, and at this point an aqueous solution of a salt of an isocytosine derivative to be tested for its effect on contractions of uterine tissue was added to the bath. Figures 1-6 are kymographic records of contractions; of the strip of uterine tissue before and after addition to the bath. of the compounds to be tested. Normal contractions are recorded in the figures up to the point designated a and at thisi time a portion of the compound to be tested was added to the bath. The portion of the figures between letters a and b represents a record ofcontractions after addition to the bath of the compound being tested. The letter b in the-figures designates the time at which the bath containing the compound be- I, II, and III, respectively, as the hydrochloride."

salts thereof. Figure 1 shows the addition to the bath of 5 milligrams of compound I in the form. v of its hydrochloride salt produced a marked increase in amplitude of contractions, some increase in tonus, and a small increase in frequency of contractions of the uterine muscular tissue.

Figure 2 shows the addition to the bath of 5;

milligrams of compound II in the form of its hydrochloride salt produced an increase in frequency of contractions, a very marked increase in tonus and some increase in amplitude of con tractions of the uterine muscular tissue. Figure 3 shows the addition to the bath of 5 milligrams of compound III-in the form of its hydrochloride salt produced a very marked increase in amplitude of contractions, a substantial increase in frequency of contractions, and a marked'increase in tonus of the uterine muscular tissue.

Figures 4, 5, and 6 show only slight efiects on the uterine muscular tissue result from the addition of sesquisucci-nate salts "of compounds IV, V, andVI to the bath; Figure 4 shows the addition of 10 milligrams of the sesquisuccinate salt of compound IV produced a slight decrease in amplitude of contractions and Figures 5 and 6 show the addition to the bath of 10 milligrams of the sesquisuccinate salts of compounds V and respectively, produced a slight increase in amplitudeof contractions and a slight increase in terms of the uterine muscular tissue.

Tonus is a natural property of muscle and is a measure of degree'of contraction independent of external influences. The degree of contraction produced by a stimulant depends upon the level of tonus, and, therefore, some investigators have defined "tonus as theresistance offered -to extension.

Amplitude may .be defined as the height of a contraction wave measured from the base level to the peak of the wave; base level being the average lower level of-the contractions.

Frequency is thenumber of contraction'waves gin a-um'ttime period. a Y Derivatives. of isocytosine such as 2- amino-4- -dialkylaminopropoxypyrimidine maybe prepared by reacting 2-amino-4-chloropyrimidine with the 4 sodium salt of a dialkylaminopropanol. The following is an example of the preparation of 2- amino-i-di-n-propylaminopropoxypyrimidine, in which the parts are given by weight. Twentyfive parts of sodium metal were slowly added to 175 parts of di-n-propylaminopropanol, dissolved in 500.parts of-xylene.' Five hundred parts of benzene were then added to the resulting sodium salt of di-n-propylaminopropanol. One hundred twenty-nine parts of 2-amino-4-chloropyrimidine wereadded to the above solution and duringthe addition the solution was cooled sufiiciently to maintain the temperature at C. After the additionwas complete, the reaction mixture wasQre'flu'xed for one hour and cooled and then "pa'rts' of water containing 10 parts ,of dissolved sodium hydroxide were added with stirring. At this point two layers were formed; the organic layer was decanted, dried over anhydrous potassium carbonate, and the solvents, benzene and xylene. were removed by distillation.- The residuein the distillation flask was distilled at a temperature of 125 C. and a pressure of 0.002 mm. of mercury. One hundred seventy-four parts of '2-amino-4-di-n-propylaminopropoxypyrimidine were obtained. The free pyrimidine base was only slightly soluble in water but reacted readily with hydrochloric acid in equimolar amounts to' produce a water-soluble hydrochloridesalt.

What is-claimed is:

1. A compound having the structural formula in which R and R each representan alkyl group having at least three but not more thanfive carbon atoms. 2., A compound according to claim 1 in which and R are each a normal propyl radical. 3. A compound accordingto claim 1 in which R and R. are each a normal butyl radical.

4. A compound according to claim 1 in which R and R are each a normal amyl radical.

, WILLIAM O'ROSHNIK.

REFERENCES CITED The following references are of record in the file of this patent:'

"Sutherland et 2.1.: J. Org. chem-"14, 235-238 (1949).

Non-Patent Citations
Reference
1 *None
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3980781 *Dec 13, 1971Sep 14, 1976Imperial Chemical Industries LimitedFungicidal composition and method containing 2-amino-pyrimidines
US4000138 *Jan 21, 1976Dec 28, 1976Imperial Chemical Industries LimitedFungicides for plants, 2-ethylamino-4-methyl-5-butyl-6-hydroxy-pyrimidine
Classifications
U.S. Classification544/320
Cooperative ClassificationC07D239/47